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FWF Stand-alone project P-34723

Role of Plasmalogens in Ether Lipid-associated Pathologies

Project leader:
Assoc.Prof. Priv.-Doz. Mag. Katrin Watschinger, PhD
Institute of Biological Chemistry, Biocenter
Medical University of Innsbruck

National research partner:
Univ.Prof. Dr. Johannes Berger
Center for Brain Research
Medical University of Vienna

Approved: 08.03.2021
Grants awarded: 606,167.52 €
Project start: 01.06.2021
Project end: 31.05.2025
Science discipline: Medical-Theoretical Sciences, Pharmacy (100%)

Abstract:

Our body contains a huge variety of lipid molecules. Many of them have been extensively characterized regarding their function, but still there exist entire groups of lipids, whose physiological role is poorly understood. Ether lipids form such a lipid subclass. These fat molecules closely resemble triglycerides, the main energy storage fats in our body, but in contrast to the three fatty acid residues attached to glycerol in triglycerides, ether lipids have two fatty acids and an alcoholic unit connected to the glycerol backbone. There are rare inherited diseases, which lead to a complete lack of ether lipids in the body. Children suffering from such disorders have a broad spectrum of severe symptoms leading to death still during childhood.

Ether lipids can be categorized into two classes. One are the saturated ether lipids, the plasmanyl lipids. These saturated ether lipids are the targets of a particular enzyme, which introduces a double bond adjacent to the linkage of the alcoholic unit to the glycerol backbone thus yielding plasmenyl lipids, also called plasmalogens. Plasmalogens presumably play multiple roles in the human body and have also been implicated to be involved in neurodegenerative disorders like Alzheimer’s and Parkinson’s disease. The enzyme which introduces this double bond is plasmanylethanolamine desaturase (PEDS1), which was an orphan enzyme until 2020, when we identified the gene coding for it. The knowledge on the gene encoding PEDS1 now enables us to compare the effect of the lack of all ether lipids (plasmanyl and plasmenyl) in cells and model organisms, obtained by manipulation of an enzyme early in the biosynthesis of ether lipids, to the effect of a specific lack of only plasmalogens. The latter we achieve by a targeted knockout of the PEDS1 enzyme, whose genetic identity is now revealed for the first time. Through our investigations we will learn more about the functions of both subclasses of ether lipids. Based on this, we can then unravel the development of the various symptoms of ether lipid deficient patients, specifically the disturbances in the neuronal system and behavior, the eye, in fertility, bone structure and fat cell maturation. Ultimately, this should lead to novel therapeutic targets in the future.

This project is ground-breaking on the one hand due to its main scientific goal, namely understanding the role of ether lipid subclasses in physiology, now accessible for the first time due to the description of the gene coding for PEDS1; and on the other hand because two leading laboratories in the field of ether lipids from Innsbruck and Vienna join forces in order to bring ether lipid research to the forefront of science in Austria.